The interplay between a pathogen and its natural host is exquisitely complex and delicate and much of this is lost when mispaired. Ectromelia virus (ECTV), the causative agent of mousepox (the smallpox of the mouse) is one of the few models available of a natural mouse pathogen that infects through the periphery and spreads through the lymphatic system to become systemic and cause disease. There are two major mechanisms that prevent mousepox. A) Natural or innate resistance, whereby some mouse strains survive a first encounter with ECTV without major symptoms of mousepox. B) Acquired resistance, whereby mousepox susceptible mice are protected by previous exposure to ECTV or vaccination. Project 2 of this U19 has two wide Aims. In Aim 1 we will investigate the mechanisms whereby Type I IFNs (TI-IFNs) contribute to natural resistance to lethal mousepox. Completion of this Aim will give us a broad understanding about the dynamics of TI-IFN production and signaling in different organs, the importance of TI-IFN subtypes, the pathways whereby TI-IFNs are induced, the cell types that produce them, the role of local IFN signaling in the establishment of the early immune response, and the role of TI-IFNs in protecting the liver, a major target organ of the virus. In Aim 2 we will investigate the mechanisms whereby memory CD8+ T cells and humoral immunity provide acquired resistance. For CD8+ T cells, we will characterize and compare their resting state and recall response following VACV and ECTV infection and determine their mechanisms of protection. For humoral immunity, we will determine whether memory B cells can protect and whether their role is in replenishing the plasma cell compartment to generate circulating Abs, respond rapidly to virus challenge or act as APCs. In addition, we will characterize and determine the mechanisms whereby Abs to the virion and to virulence factors protect from disease. Results from Project 2 will be integrated with those of the highly complementary Projects 1 and 3 to form a comprehensive picture of the ECTV/mouse dynamic. We expect that this picture will not only provide future directions for the program, but also insight into many other virus/host relationships including that of humans with their natural pathogens.